1431612-23-5 Usage
Description
UNC 1999 is a potent, orally bioavailable, and selective inhibitor of EZH2 and EZH1, which are histone methyltransferases that play a significant role in regulating gene expression and are associated with the onset and progression of various cancers. It exhibits high selectivity over a broad range of epigenetic and non-epigenetic targets, with IC50 values of 2 nM for EZH2 and 45 nM for EZH1 in cell-free assays.
Uses
Used in Cancer Treatment:
UNC 1999 is used as an inhibitor for lysine methyltransferases EZH2 and EZH1, which are implicated in the expression of various cancers. By inhibiting these enzymes, UNC 1999 can potentially suppress tumor growth and progression.
Used in Drug Combination Therapy:
In combination with other chemotherapeutic drugs, such as gefitinib, UNC 1999 enhances the efficacy of these treatments in suppressing the proliferation of cancer cells, particularly in colon cancer.
Used in Epigenetic Research:
As a highly selective inhibitor of EZH2 and EZH1, UNC 1999 can be employed in research studies to investigate the role of these enzymes in gene regulation, cancer development, and the potential for targeted epigenetic therapies.
Used in Drug Delivery Systems:
Similar to gallotannin, UNC 1999 could potentially benefit from novel drug delivery systems to improve its delivery, bioavailability, and therapeutic outcomes in cancer treatment. Organic and metallic nanoparticles could be utilized as carriers for UNC 1999, aiming to enhance its effectiveness against cancer cells.
Features
The first orally bioavailable inhibitor against wild-type and mutant EZH2 as well as EZH1.
In vitro
UNC1999 is highly potent for both EZH2 Y641N and EZH2 Y641F mutants in vitro. UNC1999 causes concentration-dependent reductions of H3K27me3 in MCF10A cells with IC50 of 124 nM , while shows low cellular toxicity. UNC1999 displays potent, concentration-dependent inhibition of cell proliferation with EC50 of 633 nM in a DLBCL cell line harboring the EZH2Y641N mutant. In addition, biotinylated UNC1999 enriches EZH2 from HEK293T cell lysates, and thus may be used in chemoproteomics studies.
In vivo
Treatment of UNC1999 (150 and 50 mg/kg, i.p.) results in the plasma concentrations of UNC1999 above its cellular IC50 over 24 hours in vivo. In addition, UNC1999 is also orally bioavailable in mice, which makes chronic animal studies more practical and convenient.
Biochem/physiol Actions
The polycomb repressive complex 2 (PRC2), which represses gene expression through methylation of histone H3 on lysine 27 (H3K27), contains either EZH1 or EZH2 as its catalytic subunit, with EZH1 being found in both dividing and non-dividing cells, whereas EZH2 is only found in actively dividing cells. UNC1999 is an orally bioavaliable selective inhibitor of both EZH2 and EZH1 lysine methyltransferases with IC50 < 10 nM for EZH2 and 45 nM for EZH1. UNC1999 potently inhibited both wild-type and mutant Y641N EZH2 methyltransferase activity with less than a 5-fold difference in potency, and selectively killed diffused large B cell lymphoma (DLBCL) cells bearing Y641 point mutations. It was selective for EZH2 and EZH1 over 15 other lysine, arginine and DNA methyltransferases. UNC1999 is competitive with the cofactor S-adenosylmethionine (SAM) and non-competitive with the peptide substrate. Because it inhibits both EZH2 and EZH1, UNC1999 has potential advantages over EZH2 selective inhibitors in the disease settings where both PRC2 – EZH2 and PRC2 – EZH1 contribute to the methylation of H3K27. For full characterization details, please visit the UNC1999 probe summary on the Structural Genomics Consortium (SGC) website.UNC2400 is the negative control for the active probe, UNC1999. To request a sample of the negative control from the SGC, click here.To learn about other SGC chemical probes for epigenetic targets, visit sigma.com/sgc
References
1) Konze?et al. (2013),?An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1; ACS Chem. Biol.,?8?1324
2) Katona?et al. (2014),?EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells; Cancer Biol. Ther.,?15?1677
Check Digit Verification of cas no
The CAS Registry Mumber 1431612-23-5 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,4,3,1,6,1 and 2 respectively; the second part has 2 digits, 2 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 1431612-23:
(9*1)+(8*4)+(7*3)+(6*1)+(5*6)+(4*1)+(3*2)+(2*2)+(1*3)=115
115 % 10 = 5
So 1431612-23-5 is a valid CAS Registry Number.
